A synthetic polyphosphoinositide headgroup surrogate in complex with SHIP2 provides a rationale for drug discovery
Phosphoinositides regulate many cellular processes, and cellular levels are controlled by kinases and phosphatases. SHIP2 (SH2 (Src homology 2)-domain-containing inositol-phosphatase-2) plays a critical role in phosphoinositide signaling, cleaving the 5-phosphate from phosphatidylinositol 3,4,5-tris...
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sg-ntu-dr.10356-979672022-02-16T16:27:58Z A synthetic polyphosphoinositide headgroup surrogate in complex with SHIP2 provides a rationale for drug discovery Persson, Camilla Cozier, Gyles Trésaugues, Lionel Erneux, Christophe Nordlund, Pär Mills, Stephen J. Thomas, Mark P. Riley, Andrew M. Potter, Barry V. L. School of Biological Sciences DRNTU::Science::Biological sciences Phosphoinositides regulate many cellular processes, and cellular levels are controlled by kinases and phosphatases. SHIP2 (SH2 (Src homology 2)-domain-containing inositol-phosphatase-2) plays a critical role in phosphoinositide signaling, cleaving the 5-phosphate from phosphatidylinositol 3,4,5-trisphosphate. SHIP2 is thought to be involved in type-2 diabetes and obesity, conditions that could therefore be open to pharmacological modulation of the enzyme. However, rational design of SHIP2 inhibitors has been limited by the absence of a high-resolution structure. Here, we present a 2.1 Å resolution crystal structure of the phosphatase domain of SHIP2 bound to the synthetic ligand biphenyl 2,3′,4,5′,6-pentakisphosphate (BiPh(2,3′,4,5′,6)P5). BiPh(2,3′,4,5′,6)P5 is not a SHIP2 substrate but inhibits Ins(1,3,4,5)P4 hydrolysis with an IC50 of 24.8 ± 3.0 μM, (Km for Ins(1,3,4,5)P4 is 215 ± 28 μM). Molecular dynamics simulations suggest that when BiPh(2,3′,4,5′,6)P5 binds to SHIP2, a flexible loop folds over and encloses the ligand. Compounds targeting such a closed conformation might therefore deliver SHIP2-specific drugs. 2013-07-25T07:25:39Z 2019-12-06T19:48:53Z 2013-07-25T07:25:39Z 2019-12-06T19:48:53Z 2012 2012 Journal Article Mills, S. J., Persson, C., Cozier, G., Thomas, M. P., Trésaugues, L., Erneux, C., et al. (2012). A Synthetic Polyphosphoinositide Headgroup Surrogate in Complex with SHIP2 Provides a Rationale for Drug Discovery. ACS Chemical Biology, 7(5), 822-828. https://hdl.handle.net/10356/97967 http://hdl.handle.net/10220/12267 10.1021/cb200494d 22330088 en ACS chemical biology © 2012 American chemical society. |
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DRNTU::Science::Biological sciences Persson, Camilla Cozier, Gyles Trésaugues, Lionel Erneux, Christophe Nordlund, Pär Mills, Stephen J. Thomas, Mark P. Riley, Andrew M. Potter, Barry V. L. A synthetic polyphosphoinositide headgroup surrogate in complex with SHIP2 provides a rationale for drug discovery |
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Phosphoinositides regulate many cellular processes, and cellular levels are controlled by kinases and phosphatases. SHIP2 (SH2 (Src homology 2)-domain-containing inositol-phosphatase-2) plays a critical role in phosphoinositide signaling, cleaving the 5-phosphate from phosphatidylinositol 3,4,5-trisphosphate. SHIP2 is thought to be involved in type-2 diabetes and obesity, conditions that could therefore be open to pharmacological modulation of the enzyme. However, rational design of SHIP2 inhibitors has been limited by the absence of a high-resolution structure. Here, we present a 2.1 Å resolution crystal structure of the phosphatase domain of SHIP2 bound to the synthetic ligand biphenyl 2,3′,4,5′,6-pentakisphosphate (BiPh(2,3′,4,5′,6)P5). BiPh(2,3′,4,5′,6)P5 is not a SHIP2 substrate but inhibits Ins(1,3,4,5)P4 hydrolysis with an IC50 of 24.8 ± 3.0 μM, (Km for Ins(1,3,4,5)P4 is 215 ± 28 μM). Molecular dynamics simulations suggest that when BiPh(2,3′,4,5′,6)P5 binds to SHIP2, a flexible loop folds over and encloses the ligand. Compounds targeting such a closed conformation might therefore deliver SHIP2-specific drugs. |
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School of Biological Sciences |
author_facet |
School of Biological Sciences Persson, Camilla Cozier, Gyles Trésaugues, Lionel Erneux, Christophe Nordlund, Pär Mills, Stephen J. Thomas, Mark P. Riley, Andrew M. Potter, Barry V. L. |
format |
Article |
author |
Persson, Camilla Cozier, Gyles Trésaugues, Lionel Erneux, Christophe Nordlund, Pär Mills, Stephen J. Thomas, Mark P. Riley, Andrew M. Potter, Barry V. L. |
author_sort |
Persson, Camilla |
title |
A synthetic polyphosphoinositide headgroup surrogate in complex with SHIP2 provides a rationale for drug discovery |
title_short |
A synthetic polyphosphoinositide headgroup surrogate in complex with SHIP2 provides a rationale for drug discovery |
title_full |
A synthetic polyphosphoinositide headgroup surrogate in complex with SHIP2 provides a rationale for drug discovery |
title_fullStr |
A synthetic polyphosphoinositide headgroup surrogate in complex with SHIP2 provides a rationale for drug discovery |
title_full_unstemmed |
A synthetic polyphosphoinositide headgroup surrogate in complex with SHIP2 provides a rationale for drug discovery |
title_sort |
synthetic polyphosphoinositide headgroup surrogate in complex with ship2 provides a rationale for drug discovery |
publishDate |
2013 |
url |
https://hdl.handle.net/10356/97967 http://hdl.handle.net/10220/12267 |
_version_ |
1725985704901607424 |